Patent EA-004179-B1 (EA)
Title: Method of treating neoplastic disease for administration of phenylacetylglutamine, phenylacetylisoglutamine, and/or phenylacetate
IPC: A61K31/19
Filed: 1999-07-02
Abstract: 1. A pharmaceutical composition, comprising in aqueous solution (a) a compound of Formula I: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl(C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), or hydroxy and n is 0, 1, 2, 3, or 4; and b) a compound of formula III: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl (C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II; and wherein the compound of Formula I is present in a 4:1 ratio by weight to the compound of formula III and the combined concentration of the compound of Formula I and the compound of Formula III is from 200 mg/mL to 350 mg/ml. 2. The pharmaceutical composition of claim 1, wherein in the compound of Formula I, M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH; and wherein in the compound of Formula III, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 3. The pharmaceutical composition of claim 1, wherein the compound of Formula I is phenylacetylglutamine or pharmaceutically acceptable salts thereof, and the compound of Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof. 4. The pharmaceutical composition of claim 4, wherein the combined concentration is about 300 mg/mL. 5. A method of treating neoplastic disease, comprising: a) administering to a patient a pharmaceutical composition comprising: i) a compound of Formula IV: wherein n is 0-5; M is hydrogen, a salt forming cation, alkyl (C1-6), cycloalkyl, or aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), substituted aryl or hydroxy and n is 0, 1, 2, 3, or 4; and ii) a compound of Formula I: wherein n is 0-5; M is hydrogen, a salt forming cation, alkyl (C1-6), cycloalkyl, or aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II; wherein the compound of Formula IV and the compound of Formula I are present in a 4:1 ratio by weight; and iii) water sufficient to form an aqueous solution of the compound of Formula IV and the compound of Formula I wherein the combined concentration of the compound of Formula IV and the compound of formula I is from 70 mg/mL to 150 mg/mL, b) administering a composition at an infusion rate from 100 mL/hr to 400 mL/hr, wherein the composition is administered at a rate sufficient to reach a dosage level of from 0.1 g/kg/day to 2.6 g/kg/day, preferably from 0.2 g/kg/day to 0.9 g/kg/day. 6. The pharmaceutical composition of claim 5, wherein in the compound of Formula IV M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH; and wherein in the compound of Formula I, M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5 and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 7. The pharmaceutical composition of claim 5, wherein the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof, and the compound of Formula I is phenylacetylglutamine or pharmaceutically acceptable salts thereof. 8. A pharmaceutical composition, comprising in aqueous solution (a) a compound of Formula I: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl(C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), or hydroxy and n is 0, 1, 2, 3, or 4; and b) a compound of formula III: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl (C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II; and wherein the compound of Formula IV is present in a 4:1 ratio by weight to the compound of formula III and the combined concentration of the compound of Formula IV and the compound of Formula III is from 70 mg/mL to 150 mg/ml. 9. The pharmaceutical composition of claim 8, wherein in the compound of Formula IV M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH; and wherein in the compound of Formula III M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 10. The pharmaceutical composition of claim 8, wherein the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof, and the compound of Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof. 11. The pharmaceutical composition of any one of claims 7 or 10, wherein the combined concentration is about 80 mg/mL. 12. A pharmaceutical composition comprising phenylacetylglutamine, phenylacetylisoglutamine and water sufficient to form an aqueous solution in a concentration ranging from about 200 mg/mL to about 350 mg/mL. 13. A method of treating neoplastic disease, comprising: a) administering a pharmaceutical composition of any one of claims 1 to 4 or 12 to a patient at an infusion rate from 100 mL/hr to 400 mL/hr, preferably from 250 mL/hr to 300 mL/hr, wherein the composition is administered at a rate sufficient to reach a dosage level of from 0.6 g/kg/day to 25 g/kg/day, preferably from 5.0 g/kg/day to 12.0 g/kg/day. 14. A method of treating neoplastic disease, comprising: a) administering a pharmaceutical composition of any one of claims 8 to 12 or 15 to 17 to a patient at an infusion rate from 100 mL/hr to 400 mL/hr, preferably from 250 mL/hr to 300 mL/hr, wherein the composition is administered at a rate sufficient to reach a dosage level of from 0.1 g/kg/day to 2.6 g/kg/day, preferably from 0.2 g/kg/day to 0.9 g/kg/day. 15. A pharmaceutical composition, comprising an aqueous solution of a compound of Formula IV: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl(C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from substituents of Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), or hydroxy and n is 0, 1, 2, 3, or 4; and wherein the concentration of the compound of Formula IV is from 70 mg/mL to 150 mg/mL. 16. The composition of claim 15, wherein the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof. 17. The composition of claim 15, wherein the compound of Formula IV is a precursor compound of phenylacetic acid, preferably phenylbutyric acid or its pharmaceutically acceptable salts thereof.